WO1999011621A2 - Thiouree elevant les niveaux de hdl-cholesterol s'averant utilies comme agents antiatherosclereux - Google Patents

Thiouree elevant les niveaux de hdl-cholesterol s'averant utilies comme agents antiatherosclereux Download PDF

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Publication number
WO1999011621A2
WO1999011621A2 PCT/US1998/017955 US9817955W WO9911621A2 WO 1999011621 A2 WO1999011621 A2 WO 1999011621A2 US 9817955 W US9817955 W US 9817955W WO 9911621 A2 WO9911621 A2 WO 9911621A2
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Prior art keywords
hydrogen
independently
carbon atoms
lower alkyl
methyl
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PCT/US1998/017955
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English (en)
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WO1999011621A3 (fr
Inventor
Amedeo Arturo Failli
Jay Scott Shumsky
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American Home Products Corporation
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Priority to AU92110/98A priority Critical patent/AU9211098A/en
Publication of WO1999011621A2 publication Critical patent/WO1999011621A2/fr
Publication of WO1999011621A3 publication Critical patent/WO1999011621A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms

Definitions

  • This invention is directed to anti-atherosclerotic agents and more specifically to compounds, compositions and methods for treating atherosclerotic conditions, such as dyslipoproteinemias and coronary heart disease.
  • This invention specifically relates to 1- aryl-3-heteroaryl thiourea derivatives that elevate HDL cholesterol concentration and which may be useful for the treatment of atherosclerotic conditions and coronary heart disease.
  • Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke.
  • Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans ⁇ yliller et al.. Br. Med. J .. 282. 1741-1744 (1981)).
  • HDL may protect against the progression of atherosclerosis.
  • Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis. 6, 434-441 (1986)).
  • Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res.. 9, 155-167 (1968)). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al., J. Biol. Chem.. 258. 7161-7167 (1983); McKinnon et al., J. Biol. Chem., 26.
  • HDL may serve as a reservoir in the circulation of apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem.. 253, 1834-1841 (1978); Lagocki and Scanu, J. Biol. Chem.. 255. 3701-3706 (1980); Schaefer et al., J. Lipid Res.. 23, 1259-1273 (1982)).
  • agents which increase HDL cholesterol concentrations would have utility as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinemias and coronary heart disease.
  • Ureas, thioureas, and numerous derivatives thereof are known to be useful for treating various conditions.
  • the use of urea and thiourea derivatives as tyrosine kinase inhibitors to inhibit cell proliferation and differentiation in the treatment of cancer is disclosed in WO 9640673-A1.
  • the use of [(alkoxy) pyridinyl] amino derivatives to inhibit the secretion of gastric acid is disclosed in WO-9315055.
  • the use of bis-aryl ureas and related compounds as cardiovascular agents is disclosed in CA-2132771, while the administration of ureas and thioureas for the treatment of ischaemia, asthma, Parkinson's disease, epilepsy and urinary incontinence is disclosed in U.S. Patent No, 5,547,966.
  • l-(aryl- substituted)-3-(heteroaryl substituted) thioureas which are particularly useful as antiatherosclerotic agents. More particularly, this invention provides compounds of formula 1 having the structure
  • R 7 , R 8 , R 10 and R 11 are each independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms;
  • R 1 and R 12 are each independently, hydrogen or lower alkyl of 1-6 carbon atoms; and R 2 , R 3 , R 4 , R 5 and R 6 are each independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • This invention also provides methods of elevating the HDL concentration and treating or inhibiting atherosclerosis and related coronary heart disease or dyslipoproteinemias and improving the HDL/LDL cholesterol ratio in a mammal in need thereof which comprises administering to the mammal a compound of formula 1 having the structure
  • R 7 , R 8 , R 10 and R 11 are each, independently, hydrogen, halogen, or lower alkyl of 1-6 carbon atoms
  • R 1 and R 12 are each, independently, hydrogen or lower alkyl of 1-6 carbon atoms
  • R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen or lower alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • the present compounds are those represented by formula 1 :
  • R 7 , R 8 , R 9 , R 10 and R" are each, independently, hydrogen, halogen, or methyl;
  • R 1 and R 12 are hydrogen; and
  • R 2 , R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, halogen or methyl; or a pharmaceutically acceptable salt thereof.
  • lower alkyl includes both straight chain as well as branched moieties.
  • halo or halogen includes fluorine, chlorine, bromine, and iodine.
  • the term "compounds of this invention” includes the broader description encompassing the formula used in accordance with the above methods, as well as the narrower description encompassing the formula used in accordance with the above novel compounds.
  • the pharmaceutically acceptable salts of the present compounds include those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane sulfonic, toluene sulfonic and similarly known acceptable acids.
  • R R3, R4 5 R5 5 R6 an£ j R12 are as defined above and the other one of R 1 ⁇ and R 14 is a group having the formula -NRRI where R and R are as defined above; or
  • the thioacylation step is preferably carried out in an aprotic solvent for example, ethyl acetate.
  • the amine R1-1H may be used as such or as a reactive derivative, for example, a potassium or sodium salt.
  • the thioacylating agent may be a thiocarbamoyl chloride having the formula
  • R 2 is lower alkyl of 1 to 6 carbon atoms and R ⁇ , R3 ; R4 ⁇ R5 ⁇ R6 are as defined above or a thiocarbamoyl chloride having the formula R ⁇ RN-CS-Cl particularly where R* is lower alkyl of 1 to 6 carbon atoms and R is as defined above.
  • Rl2 is hydrogen
  • an optionally substituted phenyl isothiocyanate may be used as thioacylating agent.
  • R ⁇ is hydrogen
  • the l-(aryl substituted)-3-(heteroaryl substituted) thioureas of this invention may be prepared by the reaction of an appropriately substituted aryl isothiocyanate with an appropriately substituted amino heterocycle (see, e.g., J. March, Advanced Organic Chemistry. 3rd Ed., Wiley-Interscience, NY, pages 802-803).
  • the reaction may take place in an aprotic organic solvent such as dichloromethane or ethyl acetate at temperatures ranging from ambient to the reflux temperature of the solvent as shown in Scheme 1.
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described above.
  • appropriately substituted aryl isothiocyanates useful as starting materials in the reaction described above are either commercially available, known in the art, or can be readily prepared by procedures analogous to those in the literature for known compounds.
  • appropriately substituted heterocyclic amines useful as starting materials in this reaction are either commercially available, known in the art, or can be readily prepared by procedures analogous to those described in the literature for known compounds.
  • Representative compounds of this invention were evaluated in an in vivo standard pharmacological test procedure which measured the ability of the compounds of this invention to elevate HDL cholesterol levels. The following briefly describes the procedure used and results obtained.
  • Male Sprague-Dawley rats weighing 200-225 g were housed two per cage and fed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25% cholic acid and 1.0% cholesterol and water ad libitum for 8 days.
  • Each test substance was administered to a group of six rats fed the same diet with the test diet mixed in as 0.005-0.1% of the total diet. Body weight and food consumption were recorded prior to diet administration and at termination. Typical doses of the test substances were 5-100 mg/kg/day.
  • HDL cholesterol concentrations in serum were determined by separation of lipoprotein classes by fast protein liquid chromatography (FPLC) by a modification of the method of Kieft et al. (J. Lipid Res.. 32, 859-866 (1991)).
  • FPLC fast protein liquid chromatography
  • 25 mL of serum was injected onto Superose 12 and Superose 6 (available from Pharmacia), in series, with a column buffer of 0.05 M Tris (2-amino-2- hydroxymethyl-l,3-propanediol) and 0.15 M sodium chloride at a flow rate of 0.5 mL/min.
  • the eluted sample was mixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2 mL/min.
  • the combined eluents were mixed and incubated on line through a knitted coil (available from Applied Biosciences) maintained at a temperature of 45°C.
  • the eluent was monitored by measuring absorbance at 490 nm and gives a continuous absorbance signal proportional to the cholesterol concentration.
  • the relative concentration for each lipoprotein class was calculated as the percent of total absorbance.
  • HDL cholesterol concentration in serum was calculated as the percent of total cholesterol as determined by FPLC multiplied by the total serum cholesterol concentration.
  • the test compounds were administered at a dose of 100 mg/kg (Table I) and the duration of treatment was eight days. The results obtained in this standard pharmaceutical test procedure are shown below in Table 1.
  • Example 1 67
  • Example 2 87
  • Example 3 16 Example 4
  • Example 5 21 Example 6 513
  • Example 8 272 Example 9
  • Example 10 154
  • Example 11 413 Example 12 399
  • the compounds of the present invention are useful in raising the concentration of HDL cholesterol, and are therefore, useful for treating or inhibiting atherosclerosis, related cardiovascular disease, or dyslipoproteinemias, and for improving the HDL/LDL cholesterol ratio.
  • the present compounds are useful in treating several metabolic conditions associated with low concentrations of HDL, such as low HDL-cholesterol levels in the absence of dyslipidemia, metabolic syndrome, non- insulin dependent diabetes mellitus (NIDDM), familial combined hyperlipidemia, familial hypertriglyceridemia, and dyslipidemia in peripheral vascular disease (PVD).
  • NIDDM non- insulin dependent diabetes mellitus
  • PVD peripheral vascular disease
  • the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • the invention provides a pharmaceutical composition comprising a compound of this invention in association or combination with a pharmaceutically acceptable carrier.
  • the invention also provides a process for the preparation of such a pharmaceutical composition by bringing a compound of this invention into association or combination with a pharmaceutically acceptable carrier.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • their derivatives and oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition containing the present compounds is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient.
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form may also be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the therapeutically effective amount of the compounds of this invention that is administered and the dosage regimen depends on a variety of factors, including the weight, age, sex, medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain the present compounds in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and most preferably between about 1 and about 100 mg.
  • Projected daily dosages of active compound are about 0.01 to about 100 mg/kg body weight. The daily dose can be conveniently administered two to four times per day.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur des composés de structure (I) dans laquelle R1 est (II), (III), (IV) ou (V) dans lesquels R?7, R8, R9, R10 et R11¿ sont chacun indépendamment hydrogène, halogène, alkyle à 1 à 6 atomes de carbone; R?1 et R12¿ sont chacun indépendamment hydrogène ou alkyle à 1 à 6 atomes de carbone; et R?2, R3, R4, R5 et R6¿ sont chacun indépendamment hydrogène, halogène, alkyle à 1 à 6 atomes de carbone; ou sur l'un de leurs sels pharmacocompatibles.
PCT/US1998/017955 1997-09-03 1998-08-31 Thiouree elevant les niveaux de hdl-cholesterol s'averant utilies comme agents antiatherosclereux WO1999011621A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU92110/98A AU9211098A (en) 1997-09-03 1998-08-31 Thiourea for increasing hdl-cholesterol levels, which are useful as anti-atherosclerotic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92264897A 1997-09-03 1997-09-03
US08/922,648 1997-09-03

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WO1999011621A2 true WO1999011621A2 (fr) 1999-03-11
WO1999011621A3 WO1999011621A3 (fr) 1999-07-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067506B2 (en) * 2001-03-02 2006-06-27 Icos Corporation Compounds useful for inhibiting Chk1

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EP0001979A1 (fr) * 1977-10-08 1979-05-30 Shudo, Koichi, Prof. Dr. N-(chloro-2-pyridyl-4)-N'-phénylurées, leur procédé de préparation et régulateurs de croissance des plantes les contenant
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WO1996018617A1 (fr) * 1994-12-12 1996-06-20 Merck & Co., Inc. Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote
WO1996040673A1 (fr) * 1995-06-07 1996-12-19 Sugen, Inc. Nouveaux composes de type uree et thiouree

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Publication number Priority date Publication date Assignee Title
DE2557438A1 (de) * 1974-12-20 1976-06-24 Leo Pharm Prod Ltd N-substituierte n"cyano-n'pyridylguanidin-verbindungen
EP0001979A1 (fr) * 1977-10-08 1979-05-30 Shudo, Koichi, Prof. Dr. N-(chloro-2-pyridyl-4)-N'-phénylurées, leur procédé de préparation et régulateurs de croissance des plantes les contenant
US4387106A (en) * 1982-01-26 1983-06-07 American Cyanamid Company Method of treating atherosclerosis with di(aralkyl)ureas and di(aralkyl)thioureas
DD223445A1 (de) * 1984-03-18 1985-06-12 Neubauer T Paedagog Hochschule Verfahren zur herstellung von thioharnstoffderivaten
EP0528146A1 (fr) * 1991-07-01 1993-02-24 Sandoz Ltd. Dérivés de la phényl-thiourée et leur utilisation pharmaceutique
WO1996018617A1 (fr) * 1994-12-12 1996-06-20 Merck & Co., Inc. Pyridines 2-acylaminees substitutees utilisees comme inhibiteurs de synthase d'oxyde d'azote
WO1996040673A1 (fr) * 1995-06-07 1996-12-19 Sugen, Inc. Nouveaux composes de type uree et thiouree

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HEINISCH, GOTTFRIED ET AL: "Synthesis of N-aryl-N'-heteroaryl-substituted urea and thiourea derivatives and evaluation of their anticonvulsant activity" ARCH. PHARM. (WEINHEIM, GER.) (1997), 330(7), 207-210,1997, XP002087695 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067506B2 (en) * 2001-03-02 2006-06-27 Icos Corporation Compounds useful for inhibiting Chk1
US7608618B2 (en) 2001-03-02 2009-10-27 Icos Corporation Urea or thiourea substituted 1,4-pyrazine compounds useful as anti-cancer agents and for inhibiting Chk1

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AR017047A1 (es) 2001-08-22
ZA987970B (en) 2000-05-31
WO1999011621A3 (fr) 1999-07-01
AU9211098A (en) 1999-03-22

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